WO1999034801A1 - Derives de diphenylmethylene piperidine pour le traitement de la depression - Google Patents

Derives de diphenylmethylene piperidine pour le traitement de la depression Download PDF

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Publication number
WO1999034801A1
WO1999034801A1 PCT/EP1999/000145 EP9900145W WO9934801A1 WO 1999034801 A1 WO1999034801 A1 WO 1999034801A1 EP 9900145 W EP9900145 W EP 9900145W WO 9934801 A1 WO9934801 A1 WO 9934801A1
Authority
WO
WIPO (PCT)
Prior art keywords
depression
treatment
diphenylmethylene piperidine
manufacture
piperidine derivative
Prior art date
Application number
PCT/EP1999/000145
Other languages
English (en)
Inventor
Duncan Robertson Rae
John Stuart Andrews
Original Assignee
Akzo Nobel N.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to AU22790/99A priority Critical patent/AU2279099A/en
Publication of WO1999034801A1 publication Critical patent/WO1999034801A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the present invention relates to a new medical use of diphenylmethylene piperidine derivatives and, in particular to a new method of treatment for depression.
  • Depression is a major health problem in our society and also poses a tremendous financial burden on society due to lost self-support of persons suffering from depression. Life time prevalence for major depression is estimated to be between 5 to 10 %. Various forms of depression are distinguished which are separately diagnosed according to criteria given in handbooks for psychiatry, for example in the
  • Anti-depressants are distinguished from other classes, such as anxiolytics and antipsychotics. Drugs in one category may have side-effects aggravating other psychiatric diseases not belonging to the category for which the drug treatment is given.
  • the present invention provides the use of a diphenylmethylene piperidine derivative having the formula A, formula A wherein n is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prophylaxis of depression.
  • the preferred position of the fluoro atoms at the phenyl rings is at the para-position.
  • Preferred compounds are 1-[4-[4-[bis-(4-fluorophenyl)methylene]-1-piperidinyl-1- oxobutylj-pyrrolidine and 1 -[4-[4-[bis-(4-fluorophenyl)methylene]-1 -piperidinyl-1 - oxobutylj-piperidine, or a pharmaceutically acceptable salt or a solvate thereof.
  • depression is used here for the psychiatric disorder or the symptom characterised by chronic low mood and loss of capacity to experience pleasure.
  • This disease or symptom is well-recognised by a physician and can also be quantified, for example with the Hamilton Rating Scale for depression or the Montgomery and Asberg Depression Rating Scale.
  • the present invention provides a method of treating depression, which comprises treating said animal or human with a therapeutically effective amount of an above defined diphenylmethylene piperidine derivative, or a pharmaceutically acceptable acid addition salt or solvate thereof.
  • Suitable acid addition salts include hydrochloric, fumaric, maleic, methanesulfonic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation.
  • Preferred salts include the hydrochloride, the methane- sulfonate salt, and the (E) but-2-ene 1 ,4-dioate (fumarate) salt.
  • a suitable daily dose for the treatment of depression will be in the range of 0.01 - 30 mg, more usually 0.1 - 15 mg, per kg body weight of the treated person or animal.
  • the desired dose may be presented as one, two, three, four or more sub-doses administered at appropriate intervals throughout the day.
  • the present invention further provides a pharmaceutical formulation for use in the treatment of depression comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier thereof and optionally other therapeutic agents.
  • the carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof.
  • suitable carriers are various carbohydrates, gum acacia, calcium phosphate, gelatin, talc, magnesium stearate or mineral oil.
  • the invention further includes a pharmaceutical formulation as herein described, in combination with packaging material adapted for the pharmaceutical formulation, said packaging material including facilities for the use of the pharmaceutical formulation in the treatment of depression. In particular, such facilities can include precautions limiting the total dose contained in the package handed over to the person for treatment in order to reduce the risk of overdosing due the misuse of the available supply.
  • Formulations include those adapted for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et a/., Remington's Pharmaceutical Sciences (18 th ed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical Preparations and their manufacture).
  • Such methods include the process of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients, carrying out said process by exclusion of contamination with traces of pathogens and harmful chemicals.
  • Such accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents and wetting agents.
  • Formulations adapted for oral administration may be presented as discrete units such as tablets or capsules each containing a predetermined amount of active ingredient; as powder or granulates; as a solution or suspension.
  • the active ingredient may also be presented as a bolus or paste, or may be contained within liposomes or microparticles.
  • Formulations for rectal administration may be presented as a suppository or enema.
  • Formulations adapted for parenteral administration include aqueous and non- aqueous sterile injection.
  • the formulations may be presented in unit-dose or multi- dose containers, for example sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier,. for example, water prior to use.
  • Formulation adapted for nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.
  • Formulations may, for example, be presented in a suitable sustained release form, for example, in a device such as the MinipumpTM.
  • the compounds of the invention may be prepared by any method known in the art for the preparation of a compound of similar structure. Typically the compounds are prepared by the methods described in WO 97/03065. The preferred compounds of the present invention are specifically disclosed therein.
  • Antidepressant-like drugs show a similar profile of action in this test: there is a decrease in overall responding, an increase in the number of food pellets earned per session and in the overall efficiency of performance (O'Donnell and Seiden, J Pharmacol Exp Ther 224: 80-88, 1983).
  • Methods Male rats of the Long Evans strain, weighing between 300-425g, are used in these experiments. The experiments are run in standard Skinner boxes. All rats have previous training in the DRL-72 procedure. Rats are divided into separate groups and the experiment undertaken using an independent groups design. The number of lever presses and pellets obtained in each 1 hour session are recorded and an efficiency score (pellets earned/responses) is calculated.
  • Statistical analysis is by one factor independent groups ANOVA, followed by post hoc Tukey HSD tests where overall significance is obtained.
  • the numbers in the table are means of 12 rats;
  • Desipramine suppresses lever pressing in a dose-related manner and significantly increases the number of food pellets obtained and overall efficiency per session. This reflects the antidepressant effect of desipramine.
  • ORG 22110 suppresses lever pressing in a dose-related manner and significantly increased the number of pellets obtained and overall efficiency per session. This reflects the antidepressant effect of Org 22110.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un dérivé de diphénylméthylène pipéridine, de formule (A) dans laquelle n vaut 1 ou 2, ou bien de son sel ou de son solvate pharmaceutiquement acceptables, pour la préparation d'un médicament destiné au traitement ou à la prévention de la dépression.
PCT/EP1999/000145 1998-01-09 1999-01-05 Derives de diphenylmethylene piperidine pour le traitement de la depression WO1999034801A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22790/99A AU2279099A (en) 1998-01-09 1999-01-05 Use of diphenylmethylene piperidine derivatives in the manufacture of a medicament for the treatment of depression

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98200037.4 1998-01-09
EP98200037 1998-01-09

Publications (1)

Publication Number Publication Date
WO1999034801A1 true WO1999034801A1 (fr) 1999-07-15

Family

ID=8233285

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/000145 WO1999034801A1 (fr) 1998-01-09 1999-01-05 Derives de diphenylmethylene piperidine pour le traitement de la depression

Country Status (2)

Country Link
AU (1) AU2279099A (fr)
WO (1) WO1999034801A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996025414A1 (fr) * 1995-02-15 1996-08-22 Pharmacia & Upjohn Company Imidazo[1,2-a]pyridines pour le traitement du snc et de cardiopathologies
WO1997000243A1 (fr) * 1995-06-15 1997-01-03 Smithkline Beecham Plc Derives de 5-aminoalkyle-2-(2-alkoxyphenyl)-pyrrole comportant une affinite pour des recepteurs de dopamine d3 et leur utilisation pour le traitement des psychoses
WO1997003065A1 (fr) * 1995-07-12 1997-01-30 Akzo Nobel N.V. Derives de diphenylmethylene piperidine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996025414A1 (fr) * 1995-02-15 1996-08-22 Pharmacia & Upjohn Company Imidazo[1,2-a]pyridines pour le traitement du snc et de cardiopathologies
WO1997000243A1 (fr) * 1995-06-15 1997-01-03 Smithkline Beecham Plc Derives de 5-aminoalkyle-2-(2-alkoxyphenyl)-pyrrole comportant une affinite pour des recepteurs de dopamine d3 et leur utilisation pour le traitement des psychoses
WO1997003065A1 (fr) * 1995-07-12 1997-01-30 Akzo Nobel N.V. Derives de diphenylmethylene piperidine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BERKOW ET AL: "The Merck Manual", 1992, MERCK RESEARCH LABORATORIES, USA, XP002070993 *

Also Published As

Publication number Publication date
AU2279099A (en) 1999-07-26

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